This invention relates to certain novel imidazoline compounds and analogues thereof, to their use for the treatment of diabetes, diabetic complications, metabolic disorders, or related diseases where impaired glucose disposal is present, to pharmaceutical compositions comprising them, and to processes for their preparation.
It is generally accepted that the control of blood glucose levels for the treatment of patients diagnosed with type II diabetes will have a beneficial effect. Established oral therapies for treating type II diabetes either improve insulin action or cause enhanced insulin secretion. The agents currently approved as therapies for type II diabetes patients that cause an enhanced insulin secretion contain a sulphonlyurea moiety. These compounds act by depolarising the beta cell by modulating closure of the K-ATP channel. Additional compounds that act at the K-ATP channel are under consideration for treatment of type II diabetes and that are not sulphonylurea compounds and have a fast onset of activity and short duration of action such as (xe2x88x92)-N-(trans4-isopropylcyclohexanecarbonyl)-D-phenylalanine (A-4166) (Brit. J. Pharm. 1997,120,137-145).
All agents that function at the molecular level by modulating the K-ATP channel have the potential for inducing hypoglycemia. Hypoglycemia is the major cause of adverse reactions in patients receiving sulphonylurea therapy and the prevalence of hypoglycemic episodes can be as high as 20% of patients. Compounds that potentiate insulin secretion under high glucose conditions and have little or no effect at low blood glucose levels would offer a distinct advantage in the treatment of type II diabetes.
Compounds of the present invention potentiate the secretion of insulin from beta cells under high glucose conditions and have minimal effect under low glucose conditions.
The compounds are also operable in additional disease states where impaired glucose disposal is present. For example, these include cardiovascular disease where above normal glucose levels are present or initial insulin resistance has occurred. The compounds can also be used to treat post operative insulin resistance induced by anaesthesia.
The present invention provides compounds of the following Formula (I), and the use of said compounds in the treatment of diabetes, especially Type II diabetes, diabetic complications, and metabolic disorders or related diseases in particular where impaired glucose disposal is present. 
wherein
X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NR5xe2x80x94;
R5 is hydrogen, C1-8 alkyl, or an amino protecting group,
R1, R1xe2x80x2, R2, and R3 are independently hydrogen or C1-8 alkyl;
R1and R2 optionally together form a bond and R1xe2x80x2 and R3 are independently hydrogen or C1-8 alkyl;
R1 and R2 optionally combine together with the carbon atoms to which they are attached form a C3-7 carbocyclic ring and R1xe2x80x2 and R3 are independently hydrogen or C1-8 alkyl;
R1 and R1xe2x80x2 together with the carbon atom to which they are attached optionally combine to form a C3-7 spirocarbocyclic ring and R2 and R3 are independently hydrogen or C1-8 alkyl;
R2 and R3 together with the carbon atom to which they are attached optionally combine to form a C3-7 spirocarbocyclic and R1 and R1xe2x80x2 are independently hydrogen or C1-8 alkyl;
n is 0, 1, or 2;
m is 0, 1 or 2;
mxe2x80x2 is 0, 1, or 2;
qxe2x80x2 is 0,1,2,3,4, or 5;
R4 is 
Y is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NR8xe2x80x94;
Yxe2x80x2 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94;
R6 and R7 are independently hydrogen, C1-8 alkyl, C3-7 cycloalkyl, C1-8 alkoxy, C1-8 alkylthio, halo C1-8 alkylthio, C1-8 alkylsulfinyl, C1-8 alkylsulfonyl, C3-7 cycloalkoxy, aryl-C1-8 alkoxy, halo, halo-C1-8 alkyl, halo-C1-8 alkoxy, nitro, xe2x80x94NR10R11, xe2x80x94CONR10R11, aryl C1-8 alkyl, optionally substituted heterocyclyl, optionally substituted phenyl, optionally substituted naphthyl, optionally halo substituted acylamino, cyano, hydroxy, COR12, halo C1-8 alkylsulfinyl, or halo C1-8 alkylsulfonyl, or alkoxyalkyl of the formula
CH3(CH2)pxe2x80x94Oxe2x80x94(CH2)qxe2x80x94Oxe2x80x94;
xe2x80x83where
p is 0, 1, 2, 3, or 4; and
q is 1, 2, 3, 4, or 5;
R12 is C1-8 alkyl or optionally substituted phenyl;
R8 is hydrogen, C1-8 alkyl, halo-C1-8 alkyl, optionally substituted phenyl, optionally substituted heterocyclyl, COO C1-8 alkyl, optionally substituted COaryl, COC1-8 alkyl, SO2C1-8 alkyl, optionally substituted SO2 aryl, optionally substituted phenyl-C1-8 alkyl, CH3(CH2)pxe2x80x94Oxe2x80x94(CH2)qxe2x80x94Oxe2x80x94;
R9 is hydrogen, halo, C1-8 alkyl, halo C1-8 alkyl, C1-8 alkylthio, halo C1-8 alkylthio, C3-7 cycloalkylthio, optionally substituted arylthio or heteroarylthio, C1-8 alkoxy, C3-7 cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, or optionally substituted aryl or heteroaryl, C3-7 cycloalkyl, halo C3-7 cycloalkyl, C3-7 cycloalkenyl, cyano, COOR10,CONR10R11 or NR10R11, C2-6 alkenyl, optionally substituted heterocyclyl, optionally substituted aryl C1-8 alkyl, optionally substituted heteroaryl C1-8 alkyl in which the alkyl group can be substituted by hydroxy, or C1-8 alkyl substituted by hydroxy,
R10 and R11 are independently hydrogen, C1-8 alkyl, optionally substituted aryl C1-8 alkyl, optionally substituted phenyl, or R10 and R11 together with the nitrogen atom to which they are attached may combine to form a ring with up to six carbon atoms which optionally may be substituted with up to two C1-8 alkyl groups or one carbon atom may be replaced by oxygen or sulfur;
R14 and R16 are independently hydrogen, halo, C1-8 alkyl, C3-7 cycloalkyl, C3-7 cycloalkoxy, C3-7 cycloalkylC1-8 alkoxy, halo-C1-8 alkyl, halo-C1-8 alkoxy, C1-8 alkoxy, carbo(C1-8)alkoxy, optionally substituted aryl, or optionally substituted heteroaryl;
R15 and R17 are independently hydrogen, halo, C1-8 alkoxy, C3-7-cycloalkyl, C3-7 cycloalkylC1-8 alkoxy, C1-8 alkyl, C3-7 cycloalkoxy, hydroxy, halo C1-8 alkoxy, carbo(C1-8)alkoxy, optionally substituted phenyl, optionally substituted phenyl-C1-8 alkyl, optionally substituted phenyloxy, optionally substituted phenyl-C1-8 alkoxy, (tetrahydropyran-2-yl)methoxy, C1-8 alkyl-S(O)mxe2x80x94, optionally substituted aryl-C1-8 alkyl-S(O)mxe2x80x2xe2x80x94, CH3(CH2)pxe2x80x94Z1xe2x80x94(CH2)qxe2x80x94Z2xe2x80x94, or Z3xe2x80x94(CH2)qxe2x80x2xe2x80x94Z2xe2x80x94;
Z1 and Z2 are independently a bond, O, S, SO, SO2, sulphoximino, or NR10;
Z3 is hydroxy, protected hydroxy, NR10 R11, protected amino, SH or protected SH;
provided that when R1, R1xe2x80x2, R2 and R3 are all hydrogen; n is 0; R4 is naphthyl; and R14, R15 and R16, or R15, R16 and R17 are all hydrogen, then R17 or R14, respectively, is other than halo, methoxy, or C1-6 alkyl.
and pharmaceutically acceptable salts and esters thereof.
One embodiment of the present invention is the use of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for treating diabetes or a related disorder.
Another embodiment of the present invention is a method of treating diabetes or a related disorder, which comprises administering to a patient a compound of formula (I), or a pharmaceutically acceptable salt thereof.
In the above formulae, a xe2x80x9cC1-8 alkylxe2x80x9d group can be any alkyl group, branched or unbranched, containing up to eight carbon atoms, and examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. Preferred values of C1-8 alkyl are C1-6 alkyl, and most preferably methyl and ethyl.
A xe2x80x9cC3-7 cycloalkylxe2x80x9d group is cyclopropyl, cyclobutyl, cyclohexyl or cyclopentyl.
A xe2x80x9cC3-7 cycoalkyl-C1-8 alkylxe2x80x9d group is one such cycloalkyl group attached through a C1-8 alkyl group (an alkylene group) to the ring.
A xe2x80x9cC1-8 alkoxyxe2x80x9d group is one of the above-mentioned C1-8 alkyl groups attached through oxygen to the ring, and preferred examples are methoxy and ethoxy.
A xe2x80x9cC3-7 cycloalkoxyxe2x80x9d group is a C3-7 cycloalkyl group as mentioned above linked through an oxygen atom to the ring as, for example, cyclopropyloxy, cyclopentyloxy and cyclohexyloxy.
A xe2x80x9cC3-7 cycloalkylC1-8 alkoxyxe2x80x9d group is a C3-7 cycoalkyl-C1-8 alkyl as mentioned above linked through an oxygen atom to the ring as, for example, cyclohexylmethoxy.
A xe2x80x9ccarbo(C1-8)alkoxyxe2x80x9d group is a 
group, for example a carbomethoxy or carboethoxy group.
An xe2x80x9coptionally substituted arylxe2x80x9d group is a mononuclear or polynuclear aromatic hydrocarbon group, for example phenyl or naphthyl, which is optionally substituted with one or more, preferably one to three, substituents independently selected from, for example, C1-8 alkyl, C1-8 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, amino, and phenyl which is optionally substituted by from one to three independently selected from the group consisting of C1-8 alkyl, C1-8 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and amino.
xe2x80x9cHeteroarylxe2x80x9d means about a four to about a ten membered aromatic mononuclear or polynuclear ring system in which one or more of the atoms in the ring is an element other than carbon, for example nitrogen, oxygen, or sulfur. Examples of heteroaryl groups include indolyl, imidazolyl, furanyl, thiophenyl, benzofuranyl, benzothiopenyl, pyridyl, quinolinyl, oxazolyl, pyrrolyl, isoxazolyl, pyrimidyl, thiazolyl, and benzimidazolyl. An xe2x80x9coptionally substituted heteroarylxe2x80x9d group is a heteroaryl group which is optionally substituted with one or more, preferably one to three, substituents independently selected from, for example, C1-8 alkyl, C1-8 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, amino, and phenyl which is optionally substituted by from one to three substituents independently selected from the group consisting of C1-8 alkyl, C1-8 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and amino.
xe2x80x9cOptionally substituted heterocyclylxe2x80x9d means about a four to about a 10 membered mononuclear or polynuclear saturated or partially unsaturated ring system in which one or more of the atoms in the ring is an element other than carbon, for example nitrogen, oxygen, or sulfur, and which is optionally substituted with one or more, preferably one to three, substituents independently selected from, for example, C1-8 alkyl, C1-8 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, amino, and phenyl which is optionally substituted by from one to three substituents independently selected from the group consisting of C1-8 alkyl, C1-8 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro, phenyl, 3,4-methylenedioxy, and amino. Examples of heterocyclyl groups inicude piperidyl, imidazolidinyl, tetrahydrofuranyl, morpholinyl, homopiperidinyl, tetrahydroquinolinyl, dioxanyl, and tetrahydranpyranyl.
An xe2x80x9caryl-C1-8 alkylxe2x80x9d group can be, for example, optionally substituted phenyl-C1-8 alkyl or optionally substituted naphthyl-C1-8 alkyl, such optionally substituted groups being optionally substituted with one or more, preferably one to three, substituents selected from, for example, C1-8 alkyl, C1-8 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, SCH3, nitro and amino. A preferred aryl-C1-8 alkyl group is optionally substituted phenyl-(CH2)xxe2x80x94 where x is 1 or 2, most preferably optionally substituted benzyl.
A halo group is preferably chloro, bromo or fluoro.
A halo C1-8 alkyl or halo C1-8 alkoxy group is a substituent in which one or more, preferably one to three, hydrogen atoms on the C1-8 alkyl moiety is replaced by a halo atom, preferably chloro, bromo or fluoro.
An xe2x80x9calkoxyalkoxyxe2x80x9d group is of the formula CH3(CH2)pxe2x80x94Oxe2x80x94(CH2)qxe2x80x94Oxe2x80x94, where p is 0-4 and q is 1-5, preferred examples being those in which p is 0 or 1 and q is 1-3, especially methoxyethoxy, ethoxyethoxy, ethoxypropoxy, or methoxypropoxy.
A xe2x80x9cC1-8 acylaminoxe2x80x9d substituent is preferably of the formula RCONHxe2x80x94 where RCO is any appropriate acid residue, RCO containing from 1-8 carbon atoms. Examples of R include C1-8 alkyl, in particular methyl or ethyl, acetyl being the most preferred acyl group. R can also be aryl C1-8 alkyl, especially benzyl, or R can be halo-C1-8 alkyl, especially trifluoromethyl.
The xe2x80x9cacylxe2x80x9d moiety, alone or in combination, is derived from an alkanoic acid containing from one to eight carbon atoms. The term xe2x80x9cacylxe2x80x9d also includes moieties derived from an aryl carboxylic acid.
As used herein, the term xe2x80x9caryl couplingxe2x80x9d shall mean any appropriate method for coupling two aromatic or heteroaromatic rings known to the artisan. Such methods may include, but are not limited to Stille coupling or Suzuki coupling methods. The Suzuki coupling is an especially preferred coupling method. The Suzuki method using Arxe2x80x94B(OH)2 and Pd catalyst is particularly preferred for use in the synthesis methods described herein. The artisan will appreciate that there are a variety of available Pd catalysts which are acceptable for the Suzuki coupling. One such Pd catalyst which is preferred for the methods described herein is Pd(PPh3)4 
The term xe2x80x9ctreatingxe2x80x9d, as used herein, describes the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a compound of present invention to prevent the onset of the symptoms or complications, to alleviate the symptoms or complications, or to eliminate the disease, condition, or disorder.
In the above formula (I), the moiety X is preferably xe2x80x94NR5xe2x80x94, where R5 is hydrogen or an amino protecting group, and is most preferably hydrogen, the protected derivatives being mainly useful as intermediates. Protecting groups can be any of the conventional amino protecting groups, see, for instance, T. W. Greene, Protective Groups in Organic Synthesis chapter 7, John Wiley and Sons, New York, 1981, and by J. W. Barton, Protective Groups in Organic Chemistry, chapter 2, J. F. W. McOmie, ed., Plenum Press, New York, 1973. Examples of such groups include but are not intended to be limited to benzyl and substituted benzyl such as 3,4-dimethoxybenzyl, O-nitrobenzyl, and triphenylmethyl; those of the formula xe2x80x94COOR where R includes such groups as methyl, ethyl, propyl, isopropyl, 2,2,2-trichloroethyl, 1-methyl-1-phenylethyl, isobutyl, t-butyl, t-amyl, vinyl, allyl, phenyl, benzyl, p-nitrobenzyl, O-nitrobenzyl, and 2,4-dichlorobenzyl; acyl groups and substituted acyl such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, benzoyl, and p-methoxybenzoyl; and other groups such as methanesulfonyl, p-toluenesulfonyl, p-bromobenzenesulfonyl, p-nitrophenylethyl, p-toluenesulfonylaminocarbonyl, and the like. Preferred nitrogen protecting groups are benzyl, acyl, or silyl.
It is preferred that R1 and R1xe2x80x2 are hydrogen or methyl, and R2 and R3 are hydrogen, or R1 and R1xe2x80x2 are both hydrogen, and R2 and R3 are hydrogen or methyl, and that 
of Formula (I) is an imidazolinyl group. Especially preferred imidazolines are those wherein R1, R1xe2x80x2, R2 and R3 are each hydrogen; and R5 is hydrogen or an amino protecting group.
Further preferred compounds of Formula (I), as defined hereinabove, are those which have one or more of the following independently selected features:
(i) R1and R1xe2x80x2 are hydrogen and R2 and R3 are hydrogen or methyl, more preferably R1, R1xe2x80x2, R2 and R3 are hydrogen;
(ii) X is xe2x80x94NHxe2x80x94;
(iii) n is 0;
(iv) R4 is 
xe2x80x83in which
R14 and R16 are indepedently selected from hydrogen, halo, or optionally substituted phenyl, naphthyl or thienyl, more preferably from hydrogen, bromo, chloro, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl ,4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 5-chloro-2-thienyl, 2-thienyl, 3-thienyl, 4-(trifluoromethyl)phenyl, 2,4-dimethoxyphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3-(trifluoromethyl)phenyl, biphenyl, 4xe2x80x2-chlorobiphenyl, or 3-nitrophenyl, and most preferably from hydrogen, bromo, chloro, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 5-chloro-2-thienyl, 2,4-dichlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 4-methylphenyl, 3-chloro-4-fluorophenyl, 4-(trifluoromethyl)phenyl, 2-methoxyphenyl, or 4-methoxyphenyl,
R15 is selected from hydrogen, halo, methyl, or methoxy, more preferably hydrogen, and
R17 is selected from benzyloxy, propoxy, butoxy, H3C(CH2)pxe2x80x94Oxe2x80x94(CH2)qxe2x80x94Oxe2x80x94, H3C(CH2)pxe2x80x94Sxe2x80x94(CH2)qxe2x80x94Oxe2x80x94, H3C(CH2)pxe2x80x94SO2xe2x80x94(CH2)qxe2x80x94Oxe2x80x94, (tetrahydropyran-2-yl)methoxy, cyclobutylmethoxy, cyclopentylmethoxy, or cyclohexylmethoxy, more preferably from H3Cxe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94, H3CCH2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94, H3Cxe2x80x94Oxe2x80x94(CH2)3xe2x80x94Oxe2x80x94, H3CCH2xe2x80x94Oxe2x80x94(CH2)3xe2x80x94Oxe2x80x94, or cyclobutylmethoxy, and most preferably H3Cxe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94;
(v) R4 is an indol-3-yl group of the formula 
xe2x80x83in which
R6 is selected from hydrogen, halo, nitro, cyano, C1-6 alkyl, halo C1-6 alkyl, halo C1-6 alkoxy, or halo C1-6 alkylthio, more preferably from chloro, fluoro, methyl, trifluoromethyl, or pentafluoroethyl which are in the 5-position of the indole nucleus,
R7 is hydrogen, halo, or methyl, more preferably in the 7-position of the indole nucleus, still more preferably hydrogen or chloro, and most preferably hydrogen,
R8 is hydrogen, methyl, or optionally substituted benzyl, more preferably hydrogen or 2-chlorobenzyl, and most preferably hydrogen,
R9 is hydrogen, C1-6 alkyl, halo C1-6 alkyl, optionally substituted benzyl, optionally substituted phenyl, or optionally substituted thienyl, more preferably hydrogen, methyl, trifluoromethyl, benzyl, 3-chlorobenzyl, phenyl, 4-methylphenyl, 2,4dichlorophenyl, 3-methyl-2-thienyl, 2,5-dimethyl-3-thienyl, 4-methoxyphenyl, 2-methoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 3-thienyl, 2-bromophenyl, 4-chloro-3-methylphenyl, 2,4-dimethylphenyl, 2-(trifluoromethyl)phenyl, or 3-fluorophenyl, and most preferably hydrogen, methyl, benzyl, 3-chlorobenzyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 3-methylphenyl, 4-chloro-3-methylphenyl, 4-methoxyphenyl, or 2-methoxyphenyl;
(vi) R4 is a benzofuran-3-yl (Y=O) or benzothien-3-yl (Y=S) group 
xe2x80x83in which
R6 is selected from hydrogen, halo, C1-6 alkyl, or halo C1-6 alkyl, more preferably from chloro, fluoro, methyl, or trifluoromethyl which are in the 5-position of the bicyclic nucleus, and most preferably chloro,
R9 is C1-6 alkyl or optionally substituted phenyl, more preferably methyl, 4-methylphenyl, 4-methoxyphenyl, 2-methoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, or 2-chlorophenyl, and most preferably methyl or 2-chlorophenyl;
(vii) R4 is a benzofuran-2-yl group 
in which R6 is selected from hydrogen, halo, C1-6 alkyl, or optionally substituted phenyl, naphthyl, or thienyl, more preferably from bromo, phenyl, 4-methylphenyl, 5-chloro-2-thienyl, 2-thienyl, 3-thienyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-bistrifluoromethylphenyl, 4-fluorophenyl, or 3-fluorophenyl;
(viii) R4 is a benzothien-2-yl group 
xe2x80x83in which
R6 is selected from hydrogen, halo, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy, and more preferably from hydrogen, chloro, bromo, methoxy, methyl, or trifluoromethyl, and
R9 is hydrogen, halo, C1-4 alkoxy, C1-4 alkyl, optionally substituted phenyl, naphthyl, or thienyl, or an optionally substituted phenylmethyl, optionally substituted naphthylmethyl, optionally substituted thienylmethyl, or optionally substituted pyridylmethyl group in which the methyl group is substituted by hydroxy;
(ix) R4 is a quinolin-3-yl group 
xe2x80x83in which
R14 is selected from hydrogen, halo, C1-4 alkyl, C1-4 alkoxy, or halo C1-4 alkyl, more preferably from halo, C1-4 alkyl, or trifluoromethyl, and most preferably from chloro, methyl, or trifluoromethyl in the 6-position of the quinoline nucleus, and
R16 is C1-4 alkyl, halo C1-4 alkyl, or optionally substituted phenyl, more preferably methyl, trifluoromethyl, phenyl, or 4-methylphenyl in the 2-position of the quinoline nucleus, and mostly preferably methyl.
Preferred compounds of the present invention include:
3-(4,5-Dihydroimidazol-2-yl)-2,5-dimethyl-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-methyl-1H-indole;
3-(4,5-Dihydroimidazol-2-yl)-2-methyl-5-trifluoromethyl-1H-indole;
3-(4,5-Dihydroimidazol-2-yl)-2-methyl-5-pentafluoroethyl-1H-indole;
5,7-Dichloro-3-(4,5-dihydroimidazol-2-yl)-2-methyl-1H-indole;
3-(4,5-Dihydroimidazol-2-yl)-5-fluoro-2-methyl-1H-indole;
3-(4,5-Dihydroimidazol-2-yl)-2-methyl-5-nitro-1H-indole;
5-Bromo-3-(4,5-dihydroimidazol-2-yl)-2-methyl-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-phenyl-1H-indole;
5,7-Dichloro-3-(4,5-dihydroimidazol-2-yl)-2-phenyl-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-7-methyl-2-phenyl-1H-indole;
5-Chloro-2-(4-chlorophenyl)-3-(4,5-dihydroimidazol-2-yl)-1H-indole;
5-Chloro-2-(3-chlorophenyl)-3-(4,5-dihydroimidazol-2-yl)-1H-indole;
5-Chloro-2-(2-chlorophenyl)-3-(4,5-dihydroimidazol-2-yl)-1H-indole;
2-(4-Chlorophenyl)-5,7-dichloro-3-(4,5-dihydroimidazol-2-yl)-1H-indole;
2-(2-Chlorophenyl)-3-(4,5-dihydroimidazol-2-yl)-5-fluoro-1H-indole;
2-(2-Bromophenyl)-5-chloro-3-(4,5-dihydroimidazol-2-yl)-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-(3-fluorophenyl)-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-(4-iodophenyl)-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-(4-methylphenyl)-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-(3-methylphenyl)-1H-indole;
5,7-Dichloro-3-(4,5-dihydroimidazol-2-yl)-2(3-methylphenyl)-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-(2-methylphenyl)-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-(2-trifluoromethylphenyl)-1H-indole;
2-(2,4-Dichlorophenyl)-3-(4,5-dihydroimidazol-2-yl)-5-fluoro-1H-indole;
3-(4,5-Dihydroimidazol-2-yl)-2-(2,4-dimethylphenyl)-5-fluoro-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-(2,4-dimethylphenyl)-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-(2,5-dimethylphenyl)-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-(2-methoxyphenyl)-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-(4-methoxyphenyl)-1H-indole;
5-Chloro-2-(4-chloro-3-methylphenyl)-3-(4,5-dihydroimidazol-2-yl)-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-(4-(2-methoxyethoxy)phenyl)-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-(2-(2-methoxyethoxy)phenyl)-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-1H-indole;
5-Chloro-2-cyclohexyl-3-(4,5-dihydroimidazol-2-yl)-1H-indole;
5-Chloro-2-(cyclohexen-1-yl)-3-(4,5-dihydroimidazol-2-yl)-1H-indole;
2,5-Bistrifluoromethyl-3-(4,5-dihydroimidazol-2-yl)-1H-indole;
2-Benzyl-5-chloro-3-(4,5-dihydroimidazol-2-yl)-1H-indole;
5-Chloro-2-(2-chlorobenzyl)-3-(4,5-dihydroimidazol-2-yl)-1H-indole;
5-Chloro-2-(3-chlorobenzyl)-3-(4,5-dihydroimidazol-2-yl)-1H-indole;
5-Chloro-1-(2-chlorobenzyl)-3-(4,5-dihydroimidazol-2-yl)-2-methyl-1H-indole;
5-Chloro-3-(4,5-dihydro-4,4-dimethylimidazol-2-yl)-2-methyl-1H-indole;
5-Chloro-2-(2-chlorophenyl)-3-(4,5-dihydro-4,4-dimethylimidazol-2-yl)-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-pyridin-4-yl)-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-(3-thienyl)-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-(2,5-dimethyl-3-thienyl)-1H-indole;
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-(3-methyl-2-thienyl)-1-indole;
2-[2-(2-(2-Fluorophenyl)indol-3-yl)ethyl]-4,5-dihydroimidazole;
2-[2-(2-(2-Chlorophenyl)indol-3-yl)ethyl]-4,5-dihydroimidazole;
2-[5-Chloro-2-(2-chlorophenyl)benzofuran-3-yl]-4,5-dihydro-1H-imidazole;
2-[5-Chloro-2-(3-chlorophenyl)benzofuran-3-yl]-4,5-dihydro-1H-imidazole;
2-[5-Chloro-2-methylbenzofuran-3-yl]-4,5-dihydro-1H-imidazole;
2-[5-Fluoro-2-methylbenzofuran-3-yl]-4,5-dihydro-1H-imidazole;
2-[2-(2-Chlorophenyl)-5-fluorobenzo[b]thiophen-3-yl]-4,5-dihydro-1H-imidazole;
2-[5-Fluoro-2-(4-methylphenyl)benzo[b]thiophen-3-yl]-4,5-dihydro-1H-imidazole;
2-(5-Chloro-2-methylbenzo[b]thiophen-3-yl)-4,5-dihydro-4,4-dimethyl-1H-imidazole;
2-[7-Bromo-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[3-(2-Methoxyethoxy)-7-phenyl-naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[7-(2-Fluorophenyl)-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[7-(3-Fluorophenyl)-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[7-(4-Fluorophenyl)-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[7-(3,5-Dichlorophenyl)-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[3-(2-Methoxyethoxy)-7-(4-methylphenyl)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[3-(2-Methoxyethoxy)-7-(2-thienyl)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[3-(2-Methoxyethoxy)-7-(3-thienyl)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[7-(5-Chloro-2-thienyl)-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[7-(2-Methoxyphenyl)-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[7-(4-Methoxyphenyl)-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[3-(2-Methoxyethoxy)-7-(3-nitrophenyl)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[7-Bromo-4-chloro-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[4-Bromo-7-(5-chloro-2-thienyl)-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[4-Chloro-7-(5-chloro-2-thienyl)-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[4-Chloro-3-(2-methoxyethoxy)-7-(3-thienyl)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[4-Chloro-3-(2-methoxyethoxy)-7-(4-methylphenyl)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[4-Chloro-7-(4-chlorophenyl)-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[4-Chloro-3-(2-methoxyethoxy)-7-(3-methoxyphenyl)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[4-Chloro-3-(2-methoxyethoxy)-7-(4-trifluoromethylphenylnaphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[3-(2-Ethoxyethoxy)-7-(4-methylphenyl)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[7-(4-Methylphenyl)-3-(tetrahydropyran-2-yl)methoxynaphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[7-(4-Fluorophenyl)-3-(2-methylthioethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[7-(4-Methoxyphenyl)-3-(3-methoxypropoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[7-(5-Chloro-2-thienyl)-3-butoxynaphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[7-(5-Chloro-2-thienyl)-3-(2-ethoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[4-Bromo-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[3-(2-Methoxyethoxy)-4-(4-methylphenyl)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[4-(4-Chlorophenyl)-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[4-(2,4-Dichlorophenyl)-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[3(2-Methoxyethoxy)-4-(4-methoxyphenyl)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[3-(2-Methoxyethoxy)-4-(3methoxyphenyl)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[3-(2-Methoxyethoxy)-4-(2-methoxyphenyl)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[3-(2-Methoxyethoxy)-4-(2-thienyl)naphthalen2-2yl]-4,5-dihydro-1H-imidazole;
2-[4-(5-Chloro-2-thienyl)-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[4-Bromo-3-propoxynaphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[4-(3,4-Dichlorophenyl)-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[4-(3-Chloro-4-fluorophenyl)-3-(cyclobutylmethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
6-Chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-3-methylquinoline;
3-(4,5-Dihydro-1H-imidazol-2-yl)-3-phenylquinoline;
2-(3-Phenylbenzo[b]thiophen-2-yl)-4,5-dihydro-1H-imidazole;
2-(3-Butoxybenzo[b]thiophen-2-yl)-4,5-dihydro-1H-imidazole;
(2-(4,5-Dihydro-1H-imidazol-2-yl)benzo[b]thiophen-3yl)-(naphthalen-1-yl)methanol;
(4-tert.-Butylphenyl)-(2-(4,5-dihydro-1H-imidazol-2yl)benzo[b]thiophen-3-yl)methanol;
2-(5-Phenylbenzofuran-2-yl)-4,5-dihydro-1H-imidazole;
2-(5-(3,5-Bistrifluoromethylphenyl)benzofuran-2-yl)-4,5-dihydro-1H-imidazole;
2-(5-(4-Fluorophenyl)benzofuran-2-yl)-4,5-dihydro-1H-imidazole;
2-(5-(4-Methylphenyl)benzofuran-2-yl)-4,5-dihydro-1H-imidazole;
2-(5-(3-Thienyl)benzofuran-2-yl)-4,5-dihydro-1H-imidazole;
2-(5-(3-Fluorophenyl)benzofuran-2-yl)-4,5-dihydro-1H-imidazole;
2-(5-(3-Trifluoromethylphenyl)benzofuran-2-yl)-4,5-dihydro-1H-imidazole;
2-(5-(2-Thienyl)benzofuran-2-yl)-4,5-dihydro-1H-imidazole;
2-(5-(5-Chloro-2-thienyl)benzofuran-2-yl)-4,5-dihydro-1H-imidazole;
2-(5-(3-Methoxyphenyl)benzofuran-2-yl)-4,5-dihydro-1H-imidazole;
2-(5-(2-Methoxyphenyl)benzofuran-2-yl)-4,5-dihydro-1H-imidazole;
2-(7-(4-Methylphenyl)benzofuran-2-yl)-4,5-dihydro-1H-imidazole;
2-(7-(3-Thienyl)benzofuran-2-yl)-4,5-dihydro-1H-imidazole;
2-(7-(2-Thienyl)benzofuran-2-yl)-4,5-dihydro-1H-imidazole; and
2-(4-(5-Chloro-2-thienyl)benzofuran-2-yl)-4,5-dihydro-1H-imidazole.
More preferred compounds of the present invention include:
5-Chloro-3-(4,5-dihydroimidazol-2-yl)-2-methyl-1H-indole;
3-(4,5-Dihydroimidazol-2-yl)-2methyl-5-trifluoromethyl-1H-indole;
5-Chloro-2-(3-chlorophenyl)-3-(4,5-dihydroimidazol-2-yl)-1H-indole;
5-Chloro-2-(2-chlorophenyl)-3-(4,5-dihydroimidazol-2-yl)-1H-indole;
6-Chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-3-methylquinoline;
2-[3-(2-Methoxyethoxy)-7-(4-methylphenyl)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[3-(2-Methoxyethoxy)-7-phenyl-naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[7-(5-Chloro-2-thienyl)-3-(2-ethoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[7-(2-Fluorophenyl)-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[7-(4-Methoxyphenyl)-3-(3-methoxypropoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole;
2-[4-(4-Chlorophenyl)-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole; and
2-[4-(2,4-Dichlorophenyl)-3-(2-methoxyethoxy)naphthalen-2-yl]-4,5-dihydro-1H-imidazole.
By virtue of their acidic moieties, some of the compounds of Formula I include the pharmaceutically acceptable base addition salts thereof. Such salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkamines, and the like. Such bases useful in preparing the salts of this invention thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and the like.
Because of a basic moiety, some of the compounds of Formula I can also exist as pharmaceutically acceptable acid addition salts. Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic, acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-butyne-1, 4 dioate, 3-hexyne-2, 5-dioate, benzoate, chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hippurate, xcex2-hydroxybutyrate, glycollate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like salts.
In addition, it is recognised that compounds of the present invention may form a variety of solvates with a number of different solvents. Representative solvates can be useful as final embodiments of the present invention or as intermediates in the isolation or preparation of the final embodiments of this invention. For example solvates can be prepared with lower alcohols such as ethanol and with alkyl esters such ethylacetate.
It is recognised that various stereoisomeric forms of the compounds of Formula I may exist. The compounds may be prepared as racemates and can be conveniently used as such. Therefore, the racemates, individual enantiomers (including, but in no way limited to atropisomers), diastereomers, or mixtures thereof form part of the present invention. Unless otherwise specified, whenever a compound is described or referenced in this specification all the racemates, individual enantiomers, diastereomers, or mixtures thereof are included in said reference or description.
In addition to the pharmaceutically acceptable salts, other salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically acceptable, acid addition salts, or are useful for identification, characterisation or purification.
General methods of synthesis for the compounds of the present invention are described in Schemes I-XII below.
Compounds of formula I wherein X is NH; R1, R1xe2x80x2, R2, R3 are hydrogen; n is 1 or 2; R4 is 
R6, R7, R9 have the definitions given above can be prepared according to scheme I. 
where in R4 and n are as defined herein for Formula I, and J is C1-8alkyl, aryl, or aryl C1-8alkyl.
The transformation described in Scheme I is novel and represents an additional embodiment of the present invention and is described in Scheme Ia.
Cyclisation is induced by a silylating agent or a mixture of silylating agents, optionally in the presence of an soluble or insoluble base, e.g. triethyl amine or dimethylaminomethyl polystyrene and a solvent. Useful reagents are e.g. described in FLUKA Chemika xe2x80x9cSilylating Agentsxe2x80x9d (1995) ISBN 3-905617-08-0 and the literature cited therein.
In a more prefered embodiment, these silylating agents are trimethyl silyl halogenides, TMS-X (e.g. trimethyl silyl chloride or trimethyl silyl iodide) or hexamethyl disilazane, HMDS or trimethyl silyl diethylamine, TMS-DEA or mixtures of them. In the most prefered embodiment the reactions are carried out either in methylene chloride with excess TMS-Cl or, more prefered, TMS-I in presence of triethyl amine or dimethylaminomethyl polystyrene at ambient temperature, or in neat HMDS or HMDS/TMS-Cl 100/1, without additional base and solvent at 50xc2x0 C. to reflux, preferably at 70xc2x0 C. to 90xc2x0 C. In some cases, using TMS-X as cyclizing reagent, excessive reagent has to be added in several portions within a period of time (up to about a week) to ensure complete conversion. The process described herein is compatible to many functionalities present in an organic molecule, e.g. unprotected hydroxy, unprotected amino, olefinic double bond, cyano, nitro, aromatic halogen, amide and is sucessful in some cases, when conventional methods failed (Chem. Pharm. Bull. 1980, 28, 1394-1402). 
The process described in Scheme Ia affords numerous advantages over similar methods known in the art. The transformation can be achieved in high yield and under mild conditions, whereas, methods known in the art require the use of extreme conditions or reagents
Compounds of formula I wherein X is NH; R1, R1xe2x80x2, R2, R3 are hydrogen; n is 0; R4 is 
R6, R7, R9 have the definitions given above can be prepared according to scheme II. 
The process described in Scheme II is novel and represents another embodiment of the present invention. The process describes the preparation of imidazolines of formula I in which X is NH and R4 is an indole nucleus. The process is affected by treating a compound of formula (IV) with a compound of formula (III) in the presence of a dehydration agent between room temperature and 140xc2x0 C.; followed by treatment with an alcohol or water between room temperature and the boiling point of the reaction mixturre. The preferred compounds of formula III are 1-acetyl-imidazoline-2-one or 1-(phenyloxycarbonyl)-imidazoline-2-one. The preferred dehydration agent is phosphorus oxychloride or thionylchloride. The preferred reagent for the deprotection of the N-substituted-imidazoline or the N-substituted-imidazole is ethanol or water.
The indole nuclei of formulas (II and IV) utilized in Schemes I and II are known in the art and can be prepared as shown in the Schemes IIIa-IIIf below and as described, for example, in Bull. Soc. Chim. Fr. 1969 (4), 1227-34, with the modifications shown, for Schemes IIIa-IIId, and J. Org. Chem. (1994) 59, 6372, with the modifications shown, for Scheme IIIf; 
wherein, n, J, and R6 are as defined herein above. 
Scheme IIIg, below, describes a method for the synthesis of 3-cyanoindoles and subsequent transformation to the corresponding imidazolines, which are substituted by an aryl or heteroaryl group in position 2 of the indole nucleus. Nitrobenzene derivatives react with acetonitrile derivatives which contain a leaving group L to give (2-nitrophenyl)acetonitriles. Reactions of this type are known, for example as reported by M. Makosza et al., Liebigs Ann. Chem./Recl. 1997, 1805. Typical leaving groups L are halogens, substituted or unsubstituted phenoxy groups, or substituted or unsubstituted phenylthio groups. A preferred value for L is 4-chlorophenoxy. The reaction can be carried out with strong bases, for example, NaOH or KOH, or with alkoxylates, for example, potassium tert.-butoxide in polar solvents such as DMF or DMSO. The resulting acetonitrile is alkylated with benzyl halides or heteroarylmethyl halides, preferably bromides or chlorides. This reaction requires a base typically used for such alkylation. A preferred method uses potassium carbonate and a phase transfer catalyst, for example a crown ether. The following cyclization to 3-cyano-1-hydroxyindoles may also be carried out with strong bases in polar solvents as described above. A preferred procedure uses sodium hydroxide in DMSO. The removal of the 1-hydroxy group can be achieved under conditions which are typically used for this purpose, for example catalytic hydrogenation, reduction with metals, or with phosphorus reagents such as trialkyl phosphites, for example as reported by R. M. Acheson, in xe2x80x9cAdvances in Heterocyclic Chemistryxe2x80x9d, Vol. 51, p. 129. In a preferred method the reduction is carried out by heating with trimethyl phosphite. The transformation of the cyano group to an imidazoline is achieved by heating with ethylenediamine. This reaction is achieved, in a preferred process, with ethylenediamine tosylate by heating of both reactants at temperatures  greater than 300xc2x0 C. 
wherein R9 is aryl or heteroaryl.
Scheme IIIh describes a method for the synthesis of indol-3-yl acetates and propionates containing an aryl or heteroaryl group in the 2-position of the indole ring. Indol-3-yl acetates and propionates which are unsubstituted in position 2 are commercially available or may be prepared according to procedures known in the art, for example, in a similar manner as described in Scheme IIIb. The bromination in the 2-position of the indole nucleus may be achieved with bromination reagents and reaction conditions known in the art, for example bromine, NBS, TMS bromide/DMSO, or pyridinium bromide perbromide. A preferred method uses NBS in dichloromethane at 0xc2x0 C. 2-Bromoindoles are converted to 2-aryl or heteroaryl indoles by standard conditions known in the art for Suzuki coupling reactions using aryl or heteroaryl boronic acids employing a Pd catalyst, preferably Pd(PPh3)4. 
wherein R9 is aryl or heteroaryl, n is 1 or 2, and J is C1-4alkyl.
Compounds of Formula I, wherein X is NH; R1, R1xe2x80x2, R2, and R3 are hydrogen; n is 0; R4 is 
R14, R15, R16, and R17 have the definitions given above can be prepared by methods known in the art or as described herein. A skilled artisan would appreciate that the compounds of Formula I could be prepared from the appropriate halo and hydroxy substituted naphthalenes. Such syntheses are illustrated in Schemes IV and V, below. 
wherein R14xe2x80x2, R15xe2x80x2, and R17xe2x80x2 are R14, R15, and R17, respectively, protected derivatives thereof, or precursor moieties thereto, and R16xe2x80x2 is optionally substituted aryl, or optionally substituted heteroaryl. 
wherein R15xe2x80x2, R16xe2x80x3 and R17xe2x80x2 are R15, R16, and R17, respectively, protected derivatives thereof, or precursor moieties thereto, and R14xe2x80x3 is optionally substituted aryl, or optionally substituted heteroaryl.
Scheme VIa illustrates the introduction of the imidazoline group into the 3-position of the benzothiophene (Yxe2x95x90S) or the benzofuran nucleus (Yxe2x95x90O). The unsubstituted bicyclic heterocycle reacts with chloroformates, preferably with ethyl chloroformate to give the corresponding 3-carboxylates. The reaction is catalyzed by Lewis acids, for example, Al(III) chloride, Sn(IV) chloride, Ti(IV) chloride, or boron halides in halogenated hydrocarbons or in carbon disulfide. It should be noted that when carbon disulfide is used, intermediate dithioesters are formed as shown in Scheme VIa. A preferred method uses Al(III) chloride in carbon disulfide at room temperature. The transformation of the carboxylate or dithiocarboxylate to the imidazoline is achieved by reaction with ethylenediamine, preferably by heating in a solvent such as ethanol. This reaction is catalyzed by traces of carbon disulfide. 
Benzofurans (Yxe2x95x90O) or benzothiophenes (Yxe2x95x90S) with an optionally substituted aryl or optionally substituted heteroaryl group in the 2-position may be prepared as illustrated in Scheme VIb. The unsubstituted heterocycles are prepared by methods known in the art, preferably by heating of (2,2-dialkoxy)ethoxybenzenes or (2,2-dialkoxy)ethylthiobenzenes, respectively, in chlorobenzene with polyphosphoric acid. These intermediates are converted to the corresponding benzofuran-2-yl or benzothiophen-2-yl boronic acids using standard conditions known in the art which use metallation with butyl lithium and trapping of the carbanions with esters of boronic acid like triisopropyl borate followed by an acid work-up procedure. The following aryl coupling reaction is carried out as described above for Scheme IIIh, preferably using a Suzuki coupling method, which preferably is carried out with aryl or heteroaryl bromides or iodides. In another procedure, 2-bromobenzofurans or 2-bromobenzothiophenes are prepared using standard bromination reagents known in the art, for example NBS. In a preferred method, the heterocycles are lithiated with butyl lithium followed by trapping of the carbanions with bromine. The 2-bromoheterocycles are converted to 2-aryl or 2-heteroaryl derivatives in aryl coupling reactions with optionally substituted aryl or optionally substituted heteroaryl boronic acids. 
wherein R9xe2x80x2 is optionally substituted aryl or optionally substituted heteroaryl.
Another route to benzofurans or benzothiophenes which are substituted in the 2-position by an optionally substituted aryl or optionally substituted heteroaryl group is illustrated in Scheme VIc. Phenols or thiophenols are reacted with arylacyl bromides or heteroarylacyl bromides to give the corresponding aryl- or heteroaryloxymethyl or aryl- or heteroarylthiomethylketones, respectively. The reaction is carried out in the presence of a base, for example potassium carbonate. These intermediates are heated under acidic conditions to give the corresponding bicyclic nuclei. A preferred method is heating in polyphosphoric acid (PPA). 
wherein R9xe2x80x2 is optionally substituted aryl or optionally substituted heteroaryl.
Scheme VId describes a method for preparation of 2-methylbenzofurans or 2-methylbenzothiophenes. In the first step phenols or thiophenols, respectively, are alkylated with allyl halides which contain another leaving group L. A preferred group L is another halogen, and in a preferred method the alkylation is carried out by heating with 2,3-dichloropropene in acetone in the presence of a base, for example potassium carbonate. A preferred method for cyclization to form the heterocyclic rings is heating of the intermediate allylether or allythioether in N,N-diethylaniline. This reaction may or may not require an additional step for ring closure of the intermediate product derived from a Claisen rearrangement, for example by heating with hydrochloric acid. 
A particular method for the synthesis of benzofurans or benzothiophenes containing a 2-substituted ethyl group in position 2 of the nucleus is described in Scheme VIe. 2-Methylbenzofurans or 2-methylbenzothiophenes are brominated at the methyl group to give 2-bromomethyl derivatives by standard conditions known in the art used for benzylic brominations, preferably with NBS. These are converted to phosphonium salts by heating with phosphines, preferably by heating with triphenylphosphine to triphenylphosphonium bromides which react with aldehydes under standard conditions known in the art for Wittig reactions to give 2-vinylbenzofurans or 2-vinylbenzothiophenes. The corresponding ethyl derivatives are prepared by hydrogenation of the vinyl compounds. A preferred method uses borohydride/Ni(II) acetate, particularly borohydride which is fixed on an exchange resin. Such resins are familiar and readily commercially available from vendors known to the artisan, see for example, Bunin, B. A. (1998) The Combinatorial Index. Academic Press, San Diego. ISBN 0121413403 #10496; Gordon E. M. and Kerwin, J. F. J. (1998) Combinatorial Chemistry and Molecular Diversity in Drug Discovery. John Wiley and Sons, New York. ISBN 0471155187 #9827. 
where R9xe2x80x2CH2CH2xe2x80x94 is R9.
The synthesis of 3-chloro-2-(4,5-dihydro-1H-imidazol-2-yl)benzothiophenes is exemplified in Scheme VII. 
A procedure for the preparation of 3-optionally substituted aryl- and 3-optionally substituted heteroaryl-2-(4,5-dihydro)imidazol-2-yl benzothiophenes using a solid support is exemplified by Scheme VIIIa. The solid support illustrated in Scheme VIIIa may be a resin. Such resins and their use are familiar to the skilled artisan. Such resins can readily be obtained from commercial vendors, for example, but in no way limited to, Novabiochem, Catalog and Peptide Synthesis Handbook, 1999; Novabiochem, The Combinatorial Chemistry Catalog (March 1998); Bachem, Peptides and Biochemicals (1998). See also the following books available to the artisan via Amazon.com and from other vendors known to the skilled artisan, Terrett, N. K. (1998) Combinatorial Chemistry, Oxford University Press, New York ISBN 0198502206 #9825; Terrett, N. K. (1998) Combinatorial Chemistry, Oxford University Press, New York. ISBN0198502192#10542; Wilson, S. R., and Czarnik, A. W. (1997) Combinatorial Chemistry, Synthesis and Applications, John Wiley and Sons, Inc., New York. ISBN 047112687X#8349; and Jung, G (1996) Combinatorial Peptide and Nonpeptide Libraries: A Handbook, VCH, Weinheim; New York. ISBN 3527293809#8474. 
where R9xe2x80x2 is optionally substituted aryl or optionally substituted heteroaryl.
The synthesis of several series of benzothiophenes of the present invention is exemplified in Scheme VIIIb. 
Wherein R9xe2x80x2 is C1-8 alkyl; R9xe2x80x3 is aromatic or heteroaromatic; R9xe2x80x2xe2x80x3 is C1-8 alkyl, aromatic or heteroaromatic. As used in Scheme VIIIb, the term xe2x80x9cstrong basexe2x80x9d has the meaning as recongized by the skilled artisan. A preferred strong base is an alkyl lithium and the most preferred strong base is n-BuLi.
A procedure for preparing indoles of the present invention which are substituted in the 2-position by an optionally substituted aryl group, or optionally substituted heteroaryl group is exemplified in Scheme IX. Introduction of the ethoxycarbonylmethyl group onto the nitrobenzene is achieved by methods known in the art, for example, as described in Synthesis 1988, 1007-9. 
R9xe2x80x2 is aryl or heteroaryl; all other terms are as defined by Formula I. The term xe2x80x9calkyl phosphitexe2x80x9d shall have the meaning understood by the aritsan, and a most preferred alkyl phosphite is P(OEt)3.
Scheme X exemplifies the preparation of 6-optionally substituted aryl- or optionally substituted heteroaryl-2-imidazolinyl napthalenes. Methyl-6-bromo-2-naphthoate is converted into the imidazoline as described, for example, in Example 18, followed by introduction of the aryl or heteroaryl moiety by Suzuki reaction. The Suzuki reaction may be accomplished by methods known in the art, or by procedures described herein. 
where Ar is optionally substituted aryl or optionally substituted heteroaryl.
Scheme XI illustrates a general route for the synthesis of 2-imidazolinyl quinolines, and Scheme XII illustrates a general route for the synthesis of 3-imidazolinylquinolines. 
wherein J is C1-8alkyl, aryl, or aryl C1-8alkyl.
The artisan appreciates that, in some instances, desired isomeric forms may be obtained using separation methods which are generally known.
Compounds of Formula (I) have primary action during hyperglycemia in that they improve glucose tolerance without producing marked reduction in basal plasma glucose levels.
Compounds of the invention were active in screens for activity using assays based on the use of BTC6 cells, for example as described by Poitout, V et al. Diabetes 44:306-313 (1995) and D""Ambra, R et al Endocrinology, 126: 2815-2822 (1990)] and rat Langerhans islets, for example as described by Lacy, P. E and Kostianovsky, M. Diabetes (1967),and as described in more detail in hereinbelow, and in an Intravenous Glucose Tolerance Test as described hereinbelow.
The invention further includes a method of treating diabetes in which an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof is administered to a patient requiring such treatment.